The major aim of this project is to develop an in vivo gene therapy strategy to reverse the cognitive deficits that are present in Alzheimer's disease. As part of this proposal recent theories concerning the causes of Alzheimer's disease will be tested. The results of these investigations will make it possible to develop better science-based approaches to the prevention and treatment of Alzheimer's disease. The research focuses on the development of an in vivo gene therapy strategy to reverse the cognitive deficits induced by a glutamate receptor mutation in a mouse model system. The hypothesis that the development of Alzheimer's disease, while clearly due to multiple genetic factors such as APP, ApOE and presenilins, is also influence by additional "stresses" that contribute to the progression of the disease pathology. To test this hypothesis, mice which have been engineered to express glutamate (AMPA), receptors with an abnormally high calcium permeability as a "stress" will be engineered to over-express wild type or mutant forms of the human amyloid precursor protein (APP) which are known to cause Alzheimer's disease in humans. The mice will be analyzed for pathology and behavioral changes associated with Alzheimer's disease. The research will test a second hypothesis that has been proposed recently that nicotinic receptors of the alpha 7 sub-type are directly involved of Alzheimer's disease. Mice over-expressing mutant human amyloid precursor protein (APP will be mated to mice lacking a functional alpha 7 sub-type nicotinic receptor gene. If the hypothesis is correct, these mice should be immune to the pathological and behavioral changes seen in Alzheimer's disease.